In animals, methamphetamine is a documented dopamine (DA) neurotoxin. Whether methamphetamine is also neurotoxic in humans has not been determined, largely because of the difficulty in assessing dopamine neuronal integrity in the living human brain. Positron emission tomography (PET), when used in conjunction with neuron specific ligands, is a non- invasive imaging technique that can be used to study brain DA neurons in living humans. For example, PET imaging with [11C]WIN-35,428 has recently facilitated the successful detection of DA deficits in patients with mild Parkinson's disease, a neurodegenerative condition characterized by loss of brain DA neurons. The overall goal of the present project is to use PET imaging with (11C]WIN-35,428, in conjunction with studies of-cerebrospinal fluid dopamine metabolites, to ascertain whether humans previously exposed to high doses of methamphetamine have sustained dopaminergic neuronal injury. To achieve this goal, two series of studies are proposed. First, baboons with unilateral brain dopamine lesions of varying severity will be used to establish the sensitivity of PET for detecting decrements in DA transporter density that result from neurotoxic injury. In these studies, reductions in [11C]WIN-35,428 binding will be directly correlated with reductions in chemical and anatoMical dopamine neuronal markers measured in the same animals upon completion of the PET studies. Prior to sacrifice, baboons will also undergo lumbar puncture to determine if reductions in DA metabolites in the cerebrospinal fluid (CSF) provide a reliable index of neurotoxic DA neuronal damage in the CNS. In a second set of studies, humans with a history of exposure to high doses of methamphetamine will undergo PET and CSF studies identical to those validated in baboons. Results obtained in abstinent methamphetamine abusers will be compared to those obtained in individuals who have abused drugs other than methamphetamine, and to those collected in control subjects without a history of drug abuse or dependence. In addition, a positive control group consisting of subjects with Parkinson's disease will be studied to further validate the PET and CSF methods to be used. The proposed studies are of both scientific and practical interest. Scientifically, it is important to determine if methamphetamine-induced neurotoxic changes in the brains of animals are predictive of what will take place in the CNS of humans. From a clinical standpoint, it is important to document the consequences of drug abuse, and to know if methamphetamine abusers have damaged their brain DA systems. If they have, with age, methamphetamine abusers may be at increased risk of developing Parkinsonism, and could benefit from putative prophylactic therapies (Eldepryl, Selegiline) currently advocated for individuals who present with early signs of Parkinson's disease.